Experimental Heatstroke in Baboon: Analysis of the Systemic Inflammatory Response

Abstract

The objective of this study was to analyze the pattern of the inflammatory response to heatstroke in an experimental baboon model with a view to identifying potential target for therapeutic interventions. Blinded analysis of plasma collected from 12 juvenile baboons (Papio hamadryas) in heatstroke was used. Eight anesthetized animals were heat-stressed in an incubator at 44 degrees C to 47 degrees C until rectal temperature was 42.5 degrees C (moderate heatstroke; n = 4) or systolic arterial pressure fell to <90 mmHg (severe heatstroke; n = 4) and were allowed to recover at room temperature. Four sham-heated animals served as a control group. We performed sequential measurement of cytokines. The rectal temperature on completion of heat stress was 42.5 degrees C +/- 0.0 degrees C and 43.3 degrees C +/- 0.1 degrees C in moderate and severe heatstroke, respectively. Heat stress elicited early, simultaneous release of anti-inflammatory cytokines and chemokines (IL-10, IL-1ra, sTNFr I and II, and IL-8). Circulating levels of IL-12p40 were significantly decreased, whereas TNFalpha, IL-1beta, and IL-4 were below the detection limit in all animals. No baboon survived severe heatstroke; there was neurological morbidity without mortality in moderate heatstroke. Nonsurvivors displayed significantly greater activity/alterations in inflammation markers than survivors. Sham-heated animals had no evidence of inflammation activation. These results show that heatstroke activates complex systemic inflammatory and regulatory responses associated with outcome. Further definition of this ambivalent response is needed before identification of target of successful modulation may become possible.

Heat Stroke

“…The loss of GMWD is a consequence of increased brain water content, which is in line with the occurrence of edema in heat stroke victims. Cytoplasmic eosinophilia and nuclear pyknosis in the scattered neurons of the hippocampus and pallidum as well as in the Purkinje cells were observed in severely classic heat stroked baboons (50). The Purkinje cells of the cerebellum appear to be particularly sensitive to heat injury with the progression of cerebellar atrophy readily apparent in magnetic resonance images of heat stroke victims that experienced ataxia or other functional impairments (12,244).…”

“…Yet dehydration alone cannot account for idiosyncratic cases of exertional heat illness since other subclinical conditions (e.g., cellulitis) that had no effect on hydration level were still associated with exacerbated hyperthermia during exercise-heat stress (70). Proinflammatory cytokines, such as interleukin (IL)-1β and IL-6 are known regulators of fever during infection and are often increased in the circulation and organs of heat stroke patients and animal models (50,51,210,223). Experimental animals injected with Escherichia coli lipopolysaccharide (LPS; a nonproliferating component of the gram-negative bacteria cell wall) or Salmonella enteritidis LPS developed more rapid hyperthermia with more robust plasma IL-1β, tumor necrosis factor (TNF)α, and IL-6 responses as well as elevated liver enzymes during heat exposure compared to vehicle-injected controls (37,143,220).…”

“…The final phase of hyperthermia is characterized by a rapid increase in body temperature due to thermoregulatory breakdown that leads to collapse (279). This body temperature response is predictable and highly reproducible among experimental models and has been used to identify strain and species differences in heat stroke tolerance (50,211,212,220,223,405,406).…”

“…1; (47,214,324)]. During the past few decades, considerable emphasis has been placed on delineating the actions of cytokines in the mediation of the pathophysiological responses to heat stroke (47,50,148,152,214,223). Despite these efforts, there remain knowledge gaps in our understanding of the mechanisms mediating multi-organ damage, which has hindered identification of novel clinical strategies to treat this condition.…”

Heat stroke: Role of the systemic inflammatory response

“…Cytokines are a class of immune modulators that have been implicated in the adverse consequences of the SIRS based on data correlating high circulating levels of these proteins with heat stroke morbidity and mortality. Increased circulating levels of IL-1␣, IL-1␤, IL-1 receptor antagonist (IL-1ra, a naturally occurring receptor antagonist of IL-1), IL-6, soluble IL-6 receptor (sIL-6R), IL-8, IL-10, IL-12, interferon (IFN)-␥, tumor necrosis factor (TNF)-␣, and sTNFR concentrations are commonly observed at the time of heat stroke collapse or shortly after cooling (7,11,12,37,38,51). Elevated IFN-inducible gene expression and IFN-␥ levels are a clinical measure of viral or intracellular bacterial infection and are evident in exertional heat stroke patients with pre-existing infections (79).…”